Certain 2,4-dimethyl-5-carboxamido-thiazoles

ABSTRACT

This invention pertains to 2,4-dimethylthiazole-5-carboxamides, which have utility as fungicides and plant growth regulants. These compounds are prepared by the reaction of alpha-halo ketone derivatives with thioamides.

United "States. Patent mi Harrison et al.

[ 51 v Apr. 3, 1973 [54] CERTAIN 2,4-DlMETHYL-5- CARBOXAMIDO-THIAZOLES [75] Inventors; William A. Harrison; Marshall Knlka, both of Guelph, Ontario,

[21] Appl. No.: 33,921

Related US. Application Data [62] Division of Ser. No. 599,734, Dec. 7, 1966, Pat. No.

52 Us. ..260/302R 151 v Int.'Cl...-..' I 58 Field ofSearchNM ..260/302R [56] References Cited OTHER PUBLICATIONS Lebedeva et al. Chem. Abstracts, 56212871 (1961) Primary ExaminerAlex Mazel Assistant Examiner-R. J. Gallagher Attorney-Willard R. Sprowis 57 ABSTRACT This invention pertains to 2,4-dimethylthiazole-5-carboxamides, which have utility as fungicides and plant' growth reguiants. These compounds are prepared by the reaction of alpha-halo ketone derivativeswith thioamides.

3 Claims, No Drawings 7 alkylthiazole pounds, namely, 2-aminothiazole (I) derivatives and 2,-- derivatives, which may be (1 represented by the followingformulas:

R R R and R may be any, hydrocarbon group, whether straight chain, branched, or cyclic, whether saturated or unsaturated (aromatic unsaturation or non-benzenoid unsaturation) that is, aliphatic, cycloaliphatic and aromatic, including ethylenically unsaturated groups, among which'may be mentioned such important. groups as alkyl', aryl,- aralkyl, alkaryl, cycloalkyl, alkenyl, and various combinations thereof. R R and R may also be hydrogen; Equivalent to the hydrocarbon groups are the various substituted hydrocarbons, notably those substitutedwith halogens (e.g., chlorine, bromine), nitroi, carboxyl, ether, ester, or similar groups, singly or-as multi-substituents (e.g., R R R and/or R =2,5-dichlorophenyl; 3,4- dichlorophenyl', 2;-methyl-3,S-dichlorophenyl; 2,4,6- trimethylphenyl; 2,4,6-trichlorophenyl), as will'be exemplified in more detail below. Likewise the substitution may be in a carbon chain, for example in a ring to provide a heterocyclic ring, containing oneormore of such hetero atoms as nitrogen, oxygen, and sulfur, as

will be exemplified below. Thus, there may be mentioned such N-heterocyclic substituted products as those in which R, furfuryl, benzothiazolyl, etc. Other forms of the inventionmay be provided by joining R and R and/or R and R together'to form a ring structure, e.g., a morpholido group. If desired one or more of the Rs may serve as linkages to another like radical to form a his com pound. These embodiments are of course not exhaustive, and many other variations will be apparent to those skilled in the art.

Preferred chemicals of the invention are those in which R R and R, are hydrogen and R hasoneof the other values states, particularly alkyl(especially butyl), aryl (especiallyphenyl), alkaryl (especially tolyl, particularly o-tolyl and m-tolyl), or cycloalkyl (especially cyclohexyl), or similar hydrocarbon group havingupto 12 carbon atoms.

Alk, as used in the above formula, represents an alkyl v The compounds ,of the invention may be prepared by the well-known methods of thiazole synthesis, such as V the reaction of-alpha-halo ketones with thioureas'and thioamides. The intermediates for the preparation of the compounds 2-aminothiazole derivatives) (I) are the alpha-chloroacetoacetamides (IV) and the thioureas (V). The alpha-chloroacetoacetamides (IV) are obtained by the chlorination with sulfuryl chloride of the corresponding acetoacetamides (HI) which in turn are obtained from ethyl acetoacetate or diketene and primary or secondary amines by standard procedures. Thiourea is commercially available and the unsymmetrically substituted thioureas (V) were obtained by 'known methods. The synthesis may be represented as 7 follows:

\ II) (I CH COCHzCONRrRz-l-SOzClz CH COCHCONR|R aminothiazole (I) is filtered off, washed with water and with benzene. The arninothiazoles (:I), are insoluble in benzene and this enables their preparation from crude (IV) because the impurities present in (IV) are usually alpha-pyridyl,

or a halo or aryl substituted alkyl group. Preferably, the

benzene-soluble and may be washed. out from the end product. I I

Alternatively the reaction may be carried out in one step by mixing together III, V, and sulfuryl chloride in benzene or toluene, heating for a short time and then recovering I from its hydrochloride.

The preparation of 2-alkylthiazole derivative (II) consists of mixing an alpha-haloacetoacetamide (VI) 1 with a thioamide (VII in the presence of a suitable solvent such as alcohol, aqueous alcohol, glycol or water andheating for a short time (15 minutes to 2 hours) followed by basification'. The precipitated alkylthiazole (II') is filtered, washed and dried.

cmoocnconmar Alkyl OSNHz (VII) EXAMPLE 1 2-Amino-4-rnethyl-S-carboxanilidothiazole solution filtered and basified with ammonium hydrox ide. The precipitated base was filtered off and dried. The crude product (815 g. 87 percent yield) started to melt at 21 1 and finally melted with decomposition at 262. Recrystallization from ethanol gave 692 g. of 2 amino-4-methyl-5-thiazolecarboxanilide which started to melt at 221 or higher. Yield: 74 percent. (The purified base partially melts at 222223 and then becomes solid again. Decomposition occurs slowly as the temperature is raised and the final melting point is variable.) METHOD B A reaction mixture of alpha-chloroacetoacetanilide (528 g., 2.5 mol), thiourea (190 g., 2.5 ml) and water (1,600 ml) was stirred and heated at 8090 until the solid dissolved (about 1 hour). The hot solution was filtered and the filtrate basified with a solution of concentrated ammonium hydroxide (28 to 30 percent) (203 ml) and water (300 ml). The white precipitate was filtered, washed with water and dried. The white product melted at 220-223 and weighed 526 g. or 90 percent.

EXAMPLE 2 2-Amino-4-methyl-5 -m-methylcarboxanilidothia-zole Sulfuryl chloride (41 g.) was added in portions to a mixture of acetoacet-m-toluidide (57 g.), thiourea (46 g.) and benzene (100 ml.). Cooling was required to control the reaction. After the initial reaction had subsided the mixture was heated for 1 hr. on a steam cone andleft overnight at room temperature. Most of the benzene was evaporated from the resulting solid mass under vacuum. The solution which was obtained by treating the solid mass with warm water was filtered and basified with ammonium hydroxide. The precipitated base was collected by filtration and recrystallized from ethanol to give 33 g. or 45 percent of yellow crystals, m.p. l89-l9 1 and 193194 (double melting point).

EXAMPLE 3 2-Amino-4-methyl-S-p-methylcarboxanilidothia-zole To a stirred suspension of p-methylacetoacetanilide (40 g.) in benzene (200 ml.) was added dropwise sulfuryl chloride (30 g.) over a period of 10 minutes. The temperature was kept at -25C. by cooling. The resulting solution was stirred at room temperature for 2 hours and then the solvent was distilled off in vacuo at a temperature not greater than 50C; To the residual crude alpha-chloro-p-methylacetoacetanilide was added a solution of thiourea (25 g.) in water (50 ml.) and ethanol (100 ml.) and the mixture heated under reflux for 15 minutes. The resulting solution was basified with aqueous sodium hydroxide, the white precipitate filtered, washed with water, benzene and ethanol and dried, m.p. 234236C., yield 40 g. or 78 percent. On crystallization from ethanol it melted at 238240C.

EXAMPLE 4 2-Amino-4-methyl-5-o-chlorocarboxanilidothiazole A solution of sulfuryl chloride (33 g.) in benzene (50 ml.) was added portionwise to a flask containing 0- chloroacetoacetanilide (51 g.) and benzene (200 ml.). After the reaction mixture had stood for 2 hrs. at room temperature the benzene was removed under vacuum. To the residue, which crystallized on cooling, was added ethanol (225 ml.) and thiourea (20 g.). After the strongly exothermic reaction had subsided, the mixture was heated for 10 min. on a steam cone. A slurry of the crude hydrochloride in water was treated with aqueous ammonia to liberate the base. The base was recrystallized from ethanol, in which it is only slightly soluble, to give white crystals (55 g. or 86 percent yield) which melted at 25 8259 with decomposition.

EXAMPLE 5 2-Amino-4-methyl-5-N-ethyl-o-methylcarboxanilidothiazole To a stirred solution of N-ethyl-omethylacetoacetanilide (50 g.) in benzene (100 ml.) was added sulfuryl chloride (35 g.) dropwise over 10 minutes keeping the temperature of the reaction mixture at 25 to 30C. by cooling. The solution was allowed to stand at room temperature for 2 hours and then the solvent was distilled off in vacuo at a temperature not greater than 50. To the residual crude alphachloro-N-ethyl-o-methylacetoacetanilide was added a solution of thiourea (30 g.) in water (60 ml.) and ethanol (60 ml.) and the mixture heated under reflux for 15 minutes. The ethanol was distilled off and the aqueous residue basified with dilute aqueous sodium hydroxide. The white precipitate was filtered, washed with water and with benzene and dried, m.p. 2102 l 3 C., yield 40 g. or percent. Crystallization from benzene containing a little methanol yielded sparkling white crystals melting at 2 l 9222C.

EXAMPLE 6 2Amino-4-methyl-5 -N-benzylcarboxamidothiazole To a suspension of N-benzylacetoacetamide (30g) in benzene ml.) was added portionwise sulfuryl chloride (23 g. 11 percent excess) over 10 minutes keeping the temperature at 20-25 by cooling. The resulting solution was allowed to stand at room temperature for 2 hours and then the solvent was removed in vacuo at a temperature not greater than 50C. To the residual crude alpha-chloro N-benzylacetoacetamide was added a solution of thiourea (20 g.) in water (50 ml.) and ethanol (50 ml.) and the reaction mixture was heated under reflux for 15 minutes. The ethanol was distilled off, the aqueous residual solution was basified with sodium hydroxide, the white precipitate was filtered, washed with water and-with benzene and dried. Crystallization from isopropanol yielded 23 g. or 60, percent of white solid melting at 143145C.

EXAMPLE7 2-Amino-4-methyl-5 -N,N- dimethylcarboxarnidothiazole To a solution of N,N-dimethylacetoacetamide (40 g.) in benzene (100 ml.) was added sulfuryl chloride (45 g.) dropwise over minutes keeping the temperature of the reaction mixture at -25C. by cooling. The resulting solution was allowed to stand at room temperature for 3 hours and then the solvent was removed in vacuo at a temperature not greater than 50C. To the residual crude alpha-chloro-N,N- dimethylacetoacetamide was added a solution of thiourea g.) in water (60 ml.) and the solution was heated on the steam bath for 10 minutes. The resulting solution was treated with excess saturated aqueous sodium bicarbonate, the white precipitate filtered, washed with cold water and dried, m.p. 220225C. with decomposition; yield 30 g. or 52 percent. Crystallization from isopropanol raised the melting point to 236238C. with decomposition.

EXAMPLE 8 2-Methylamino-4-methyl-5 -car\b0xanilidothiazole A mixture of alpha-chloroacetoacetanilide (63.5 g.) methylthiourea (27 g.) and 95 percent eth'anol (150 ml.) was heated under reflux for' 2.5 hours. The solids dissolved shortly after heating commenced and then a precipitate formed. The reaction mixture was cooled and the precipitated solid filtered off. The solid, the hydrochloride of the desired product, was dissolved in warm water, the solution filtered, and the filtrate made basic with ammonium hydroxide. The precipitated base I cool, a crystalline precipitate formed which proved not to be a hydrochloride. It was filtered off and recrystallized from ethanol to give 73 g. of greyish white solid,

mp. l89-191. Yield: 78 percent.

EXAMPLE 10 This example lists-other 2-amino-4-methyl-5-carboxamidothiazoles prepared (Table l). The preparations of compounds 1, 3, 4, 6, 26, 27 and 32 are shown in detail in the previous Examples 1-7 respectively, and are representative of the methods employed for preparing the claimed compounds.

' EXAMPLE 1 1 2,4-Dimethyl-5-carboxanilidothiazole alphaChloroacetoacetanilide (21 1.5 g., 1 mole), thioacetamide g. 1 mole) and ethanol (400 ml.) were heated together under reflux on a steam bath. An exothermic reaction began soon after the mixture started to boil and the reactants were into solution within a few minutes. External heating was briefly interrup'ted until the exothermic reaction subsided and was then resumed for about 1 hour. When the reaction mixture was cooled, a precipitate of the thiazole hydrochloride formed. The hydrochloride (which can be collected by filtration at this point if desired) was dissolved again by adding some dilute hydrochloric acid and reheating the mixture. A small amount of insoluble material was removed by filtering the solution and the filtrate was basified with dilute ammonium hydroxide. The precipitated thiazole was collected by filtration, washed twice with cold 1:1 ethanol-water and dried. 175 g. (75 percent yield) of the thiazole, mp 138145. was obtained.

EXAMPLE 12 2,4-Dimethyl-5-(o-methoxycarboxanilido)thiazole A solution of sulfuryl chloride (27"g., 0.2 mole) in benzene (50 ml) was added in portions to acetoacet-oanisidide (41.4 g., 0.2 mole) in benzene ml). After the mixture had stood for an hour at room temperature the solvent was evaporated under reduced pressure. Ethanol ml) and thioacetamide (16 g., 0.21 mole) was added to the residue and the resulting mixture heated under reflux for 30 minutes. A precipitate formed after about 10 minutes of heating.

The reaction mixture was cooled and the precipitate filteredofl" and dissolved in warm, very dilute hydrochloric acid (about 25 ml of concentrated acid diluted with 750 ml of water). The solution was filtered and the filtrate made basic with ammonium hydroxide. The precipitated thiazole was collected by filtration, washed with water and a small amount of cold ethanol, and dried. The product (33 g., 63 percent yield) melted at 98.5-10l.5.

EXAMPLE 13 This example lists other 2-alkyl-4-methyl-5-carboxanilidothiazoles prepared (Table. H). The preparation of the compounds 1 and 2 are shown in detail in examples 11 and 12 respectively and are representative of the methods employed for preparing the claimed compounds of Table II.

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2. The compound of claim 1, wherein the compound is 2,4-dimethyl-5-carboxanilidothiazole.
 3. The compound of claim 1, wherein the compound is 2,4-dimethyl-5-o-methylcarboxanilidothiazole. 